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Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated. A panel of 71 genes associated with inherited cardiopathies was screened in an ACR population of 172 probands and 856 individuals from the general population. PVs and uncertain significance variants (VUS) have been identified in 36% and 18.6% of patients, respectively. Among the cardiopathy‐associated genes, burden tests show a significant enrichment in PV and VUS only for desmosomal genes PKP2 (plakophilin‐2), DSP (desmoplakin), DSC2 (desmocollin‐2), and DSG2 (desmoglein‐2). Importantly, VUS may account for 15% of ACR cases and should then be considered for molecular diagnosis. Among the other genes, no evidence of enrichment was detected, suggesting an extreme caution in the interpretation of these genetic variations without associated functional or segregation data. Genotype–phenotype correlation points to (1) a more severe and earlier onset of the disease in PV and VUS carriers, underlying the importance to carry out presymptomatic diagnosis in relatives and (2) to a more prevalent left ventricular dysfunction in DSP variant carriers. [ABSTRACT FROM AUTHOR]

Background and aims: Mutations in KCNH2 cause long or short QT syndromes (LQTS or SQTS) predisposing to life‐threatening arrhythmias. Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and patient counselling. In silico evaluation was also included to characterise the structural impact of the variants. Methods: We selected 11 variants from known LQTS patients and two variants for which diagnosis was problematic. Using the Gibson assembly strategy, we efficiently introduced mutations in hERG cDNA despite GC‐rich sequences. A pH‐sensitive fluorescent tag was fused to hERG for efficient evaluation of channel trafficking. An optimised 35‐s patch‐clamp protocol was developed to evaluate hERG channel activity in transfected cells. R software was used to speed up analyses. Results: In the present work, we observed a good correlation between cell surface expression, assessed by the pH‐sensitive tag, and current densities. Also, we showed that the new biophysical protocol allows a significant gain of time in recording ion channel properties and provides extensive information on WT and variant channel biophysical parameters, that can all be recapitulated in a single parameter defined herein as the repolarisation power. The impacts of the variants on channel structure were also reported where structural information was available. These three readouts (trafficking, repolarisation power and structural impact) define three pathogenicity indexes that may help clinical diagnosis. Conclusions: Fast‐track characterisation of KCNH2 genetic variants shows its relevance to discriminate mutants that affect hERG channel activity from variants with undetectable effects. It also helped the diagnosis of two new variants. This information is meant to fill a patient database, as a basis for personalised medicine. The next steps will be to further accelerate the process using an automated patch‐clamp system. [ABSTRACT FROM AUTHOR]

Background: Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood. Results: A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and β‐catenin. Co‐expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of β‐catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of β‐catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non‐syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased β‐catenin activities. The β‐catenin target gene, MMP2 was up‐regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype. Conclusion: Dzip1 functions to restrain β‐catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear β‐catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype. [ABSTRACT FROM AUTHOR]

Global cellular electrophysiological phenotype was then evaluated with action potential (AP) recordings, but no AP basal parameters specifically segregated BrS hiPSC-CMs, and spontaneous beating frequencies did not differ between all cell lines (Figure S4). Brugada syndrome (BrS) is an inherited arrhythmic disease predisposing to sudden cardiac death (SCD), characterized by a typical electrocardiogram pattern that includes a J point elevation with a coved type ST segment.1 BrS is a complex genetic disease in which ~20% of patients carry rare variants in I SCN5A i gene, whereas the others remain genetically unresolved.2 Despite this genetic complexity, we hypothesize that a common cellular phenotypic trait is at the root of this specific BrS ECG pattern. Importantly, the expression of I SCN5A i , the main BrS culprit gene identified to date,4 remained unchanged, excluding I SCN5A i expression levels as a hallmark for BrS hiPSC-CM phenotype. Early afterdepolarizations (EADs) were observed in 39-70% of all six BrS ventricular-like hiPSC-CMs versus only in 4% and 4.7% of Ctrl and non-BrS hiPSC-CMs, respectively (Figure 3B, Figure S5). [Extracted from the article]

Mendelian diseases have shown to be an and efficient model for connecting genotypes to phenotypes and for elucidating the function of genes. Whole‐exome sequencing (WES) accelerated the study of rare Mendelian diseases in families, allowing for directly pinpointing rare causal mutations in genic regions without the need for linkage analysis. However, the low diagnostic rates of 20–30% reported for multiple WES disease studies point to the need for improved variant pathogenicity classification and causal variant prioritization methods. Here, we present the exome Disease Variant Analysis (eDiVA; http://ediva.crg.eu), an automated computational framework for identification of causal genetic variants (coding/splicing single‐nucleotide variants and small insertions and deletions) for rare diseases using WES of families or parent–child trios. eDiVA combines next‐generation sequencing data analysis, comprehensive functional annotation, and causal variant prioritization optimized for familial genetic disease studies. eDiVA features a machine learning‐based variant pathogenicity predictor combining various genomic and evolutionary signatures. Clinical information, such as disease phenotype or mode of inheritance, is incorporated to improve the precision of the prioritization algorithm. Benchmarking against state‐of‐the‐art competitors demonstrates that eDiVA consistently performed as a good or better than existing approach in terms of detection rate and precision. Moreover, we applied eDiVA to several familial disease cases to demonstrate its clinical applicability. [ABSTRACT FROM AUTHOR]

ABSTRACT A new formulation is proposed for the electrical potential developed inside a horizontally-layered half-space for a direct current point-source at the surface. The recursion formula for the kernel coefficient in the potential integral is simpler than the generally used two-coefficient recursion. The numerical difficulties that may occur during the computation of the integrals and near the source axis are examined and solutions are proposed. The set of equations permits a stable and accurate computation of the tabular potential everywhere in the medium. [ABSTRACT FROM AUTHOR]

Background: Early repolarization in the inferolateral leads has been recently recognized as a frequent syndrome associated with idiopathic ventricular fibrillation (VF). We report the case of a patient presenting dramatic changes in the ECG in association with recurrent VF in whom a novel genetic variant has been identified. Case Report: This young female (14 years) was resuscitated in 2001 following an episode of sudden death due to VF. All examinations including coronary angiogram with ergonovine injection, MRI, and flecainide or isoproterenol infusion were normal. The patient had multiple (>100) recurrences of VF unresponsive to beta-blockers, lidocaine/mexiletine, verapamil, and amiodarone. Recurrences of VF were associated with massive accentuation of the early repolarization pattern at times mimicking acute myocardial ischemia. Coronary angiography during an episode with 1.2 mV J/ST elevation was normal. Isoproterenol infusion acutely suppressed electrical storms, while quinidine eliminated all recurrences of VF and restored a normal ECG over a follow-up of 65 months. Genomic DNA sequencing of KATP channel genes showed missense variant in exon 3 (NC_000012) of the KCNJ8 gene, a subunit of the KATP channel, conferring predisposition to dramatic repolarization changes and ventricular vulnerability. [ABSTRACT FROM AUTHOR]

Introduction: Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. Methods and Results: Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. Conclusion: The present study shows that the most common phenotype of gene carriers of a BS-type SCN5A mutation is progressive cardiac conduction defects similar to the Lenègre disease phenotype. In consequence, we propose that carriers of a SCN5A mutation need a clinical and ECG follow-up because of the risk associated with severe conduction defects. [ABSTRACT FROM AUTHOR]

Mutations in the SCN5A gene can cause Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation. We describe the case of a 3-year-old child with a structurally normal heart presenting with monomorphic ventricular tachycardia. Her electrocardiogram suggested a Brugada syndrome and the diagnosis was confirmed by the identification of a Brugada syndrome in her mother and in two other family members. Genetic study led to the identification of a c.2516T→C SCN5A mutation. The child was treated with quinidine therapy without recurrence of arrhythmic events for a time period of 16 months. [ABSTRACT FROM AUTHOR]

SCN5A Mutation and ST Segment Elevation in Inferior Leads. Mutations in the SCN5A gene can lead to the Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation that has a characteristic ECG phenotype usually restricted to precordial leads V[sub 1]–V[sub 3]. We identified a novel G752R SCN5A missense mutation leading to various degrees of the Brugada ECG phenotype in members of a French family. In the proband, the G752R mutation produced ST segment elevation and prominent J wave in leads II, III, and aVF. In four other relatives, ST segment elevation in the right precordial but not in the inferior leads was observed either spontaneously or under flecainide challenge. Recombinant G752R mutant exhibited a markedly reduced Na[sup +] current amplitude and a voltage shift in both activation and inactivation curves. The mutant was found in all affected but not in nonaffected family members. One additional gene-carrier had an almost normal ECG (silent gene-carrier). We provide genetic demonstration that Brugada ECG anomalies related to a unique SCN5A mutation can be observed either in the inferior or the right precordial leads. (J Cardiovasc Electrophysiol, Vol. 14, pp. 200-203, February 2003). [ABSTRACT FROM AUTHOR]